Process of treating herpes simplex with 1-beta-d-arabinofuranosylcytosine



United States Patent 3,397,268 PROCESS OF TREATING HERPES SIMPLEX WITHl-p-D-ARABINOFURANOSYLCYTOSINE James H. Hunter, Kalamazoo, Mich.,assignor to The Upjohn Company, Kalamazoo, Mich., a corporation ofDelaware No Drawing. Continuation-impart of application Ser. No.217,543, Aug. 17, 1962. This application Sept. 1, 1965, Ser. No. 484,473

4 Claims. (Cl. 424-180) This application is a continuation-in-part ofapplication Ser. No. 217,543, filed Aug. 17, 1962, now abandoned.

This invention relates to a pharmaceutical composition and the usethereof and more particularly to a pharmaceutical nucleoside compositionand to a process for its administration.

The inventive composition is a nucleoside composition comprising1-/3-D-arabinofuranosylcytosine and certain derivatives thereofdispersed in a pharmacetutically acceptable carrier.l-B-D-arabinofuranosylcytosine and the derivatives can be preparedaccording to the methods disclosed in copending application Ser. No.24,890, filed Apr. 27, 1960, now US. Patent No. 3,116,282. Thederivatives include the acid-addition salts, for example, those ofhydrochloric, citric, succinic, maleic, tartaric, and like acids. Of theacid-addition salts the hydrochloride is preferred. The inventivecomposition is unexpectedly active in cell culture against viruses, suchas those of pseudorabies, fowl pox, swine pox, vaccinia, herpes simplex,and B-virus. The compositions can be advantageously employed inpharmaceutical applications, for example, in treating herpes simplex inaffected mammal and bird subjects, for example, herpes simplex of theeyes.

The modes contemplated by the inventor of carrying out the inventioninclude pharmaceutical compositions suited for topical use; andprocesses of administration thereof.

Solutions of the principal active ingredient can be prepared in water orin water suitably diluted with, for example, ethanol, glycerin, polyols(for example, glycerine, polyethylene glycols, propylene glycol), andthe like. Dispersions can be prepared in gycerol, liquid polyethyleneglycols, and mixtures thereof, and in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The basic solvent or dispersion medium can contain water, ethanol,polyols (for example, glycerol, propylene glycol, and liquidpolyethylene glycol, and the like), suitable mixtures thereof, andvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersions and by the use ofsurfactants (for example, a condensation product of ethylene oxide withfatty acids or fatty alcohols, partial esters of fatty acids and ahexitol anhydride, and polyoxyethylene condensation products of theesters). The prevention of the action of microorganisms can be broughtabout by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, 'benzyl alcohol, phenol, sorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars or sodium chloride.

Sterile solutions are prepared by incorporating the principal activeingredient in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. Generally, dispersions are prepared byincorporating the previously sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and 3,397,268Patented Aug. 13, 1968 the required other ingredients from thoseenumerated above.

In the case of sterile powders for the preparation of sterile solutionsthe preferred method of preparation is the freeze-drying technique whichyields a powder of the active ingredient plus any additional desiredingredients from a previously sterile-filtered solution thereof. Thepowders can also be sterilized by the use of a gas, for example,ethylene oxide and subsequently incorporated, with the requiredadditional ingredients and in the proper particle size, into the basicpowder for later reconstitution with the desired suspending liquidwhich, of course, itself must be sterile.

The compositions suited for topical use include, for eX- ample, lotions;ointments, especially ophthalmic ointments; and ophthalmic aqueoussolutions, especially ophthalmic aqueous drops. To provide optimumcontact by the ointments, an oleaginous ointment base is used, forexample liquid petrolatum, petrolatum, and white petrolatum. Absorptionbases, such as hydrophilic petrolatum, wool fat, and hydrous wool fatcan be used also. The ophthalmic drops are sterile and may containbuffer salts providing a pH of about 7.4; and isotonic agents, forexample, sodium chloride and dextrose. Bacteriostatic agents, forexample, phenylethyl alcohol, benzalkonium chloride, chlorobutanol, andmyristyl-gamma-picolinium chloride are incorporated in the drops.

An especially useful supplementary ingredient providing more thanadditive activity in the treatment of herpes simplex of the eyes is5-iodo-2-deoxyuridine, in the proportion of from about 0.5% to about2.5% of the composition.

It is especially advantageous to formulate the inventive compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used in the specification and claims herein refersto physically discrete units suited as unitary dosages for the animaland human subjects to be treated, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. The specifications for the novel dosage unit forms of thisinvention are dictated by and direct-1y dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffeet to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for the treatment of disease inliving subjects having a diseased condition in which bodily health isimpaired a disclosed in detail in this specification, these beingfeatures of the present invention.

The dosage of the principal active ingredient for the treatment of theindicated condition depends on the age, weight and condition of thesubject being treated; the particular condition and its severity; theparticular form of the active ingredient and the route ofadministration. A dose of from about 0.1 to about 50 mgs./ kg. or adaily total dose of from about 3 to about 4000 mgs. given singly or individed doses of up to 5 times a day embraces the effective range forthe treatment of most conditions for which the compound is effective.Expressed as amounts suited for single doses, from about 3 to about 1000mgs. is operable.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically-acceptable carrier in dosage unit form as hereinbe-foredescribed. A unit dosage form can contain the principal activeingredient in amounts ranging from about 3 to about 1000 mgs. per unit.Expressed in proportion-s the active ingredient is present in from about0.5 to about 25% w./v. of the liquid compositions.

The compositions suited for topical use contain from about 0.5% to about2.5% by weight, preferably 1%.

In the case of compositions containing supplementary active ingredients,the dosage is determined by reference to the usual dose and manner ofadministration of the said ingredients.

The following examples set forth the manner and process of making andusing the inventive compositions and include the best mode contemplatedby the inventor of carrying out the invention.

EXAMPLE 5 Sterile solution A sterile aqueous solution containing 250 mg.of l-fi-D- arabinofuranosylcytosine hydrochloride in each rnl., isprepared from the following ingredients:

149-D-arabinofuranosylcytosine hydrochloride, 250 gms. Water forinjection, q.s., 1000 ml.

EXAMPLE 6 Sterile preparation A sterile aqueous preparation containing25 mg. of l-fl- D-arabinofuranosylcytosine in each 2 mls. is preparedfrom the following ingredients:

Gms. 1-1S-D-arabinofuranosylcytosine 12.5 Polyethylene glycol 4000,U.S.P. 30 Sodium chloride, U.S.P 9 Preservative, q.s.

Water for injection, q.s., 1000 ml.

EXAMPLE 10 Sterile powder for reconstitution Sterile vials eachcontaining 50 mgs. of l-fl-D-arabinofuranosylcytosine hydrochloride areprepared by first sterilizing 50 gms. of the principal active ingredientby treatment with ethylene oxide and thereafter filling 50 mgs. intoeach of 1000 sterile vials. At the time of use, the contents of a vialare reconstituted with q.s. water for injection to provide a sterilesolution for administration.

EXAMPLE 11 Ophthalmic aqueous drops 1000 milliliters of drops isprepared as follows:

Gms. l-;8-D-arabinofuranosylcytosine 10 Polyethylene glycol 4000 120'Polyvinylpyrrolidone 1 Myristyl-gamma-picolinium chloride 0.2 Water forinjection, q.s. ad., 1000 mls.

The ingredients are dissolved in the water. The resulting solution issterilized by filtration and filled aseptically in sterile containers.

The application of one drop hourly to the eye is beneficial in thetreatment of herpes simplex.

EXAMPLE 12 Ophthalmic ointment One thousand grams of ophthalmic ointmentis prepared as follows:

Gms. Wool fat 200 Liquid petrolatum 250 1-fl-D-arabinofuranosylcytosinehydrochloride 10 White petrolatum 540 Application to the affected eyesis highly beneficial in the treatment of herpes simplex keratitis inrabbits.

EXAMPLE 13 Ophthalmic ointment An ointment is prepared in accordancewith Example 12, except that the amount ofl-B-D-arabinofuranosylcytosine hydrochloride is reduced to 5 gms., and 5gms. of 5-iodo-2-deoxyuridine is incorporated. Such ointment is moreactive in the treatment of herpes simplex keratitis in rabbits eyes thanare like ointments containing 1% of 1-;8-D-arabinofuranosylcytosinehydrochloride or 1% of 5-iodo-2-deoxyuridine.

EXAMPLE l4 Lotion 1000 milliliters of a lotion is prepared as follows:

Gms. 1-/3-D-arabiuofuranosylcytosine 25 Preservative l Glycerylmonostearate, self-emulsifying (Tegacid regular) 25 Spermaceti lPurified water, U.S.P., q.s. ad. 1000 mls.

About 700 mls. of the water is heated to about 160 F. and thepreservative is dissolved therein. The glyceryl monostearate andspermaceti are added in order, while mixing homogeneously at about 160F. After cooling of the mixture, the active ingredient is added thereto,and the whole is made up to volume with the water.

The lotion is used for the treatment of herpes simplex in livingsubjects affected bodily.

EXAMPLE 15 Sterile preparation 24,000 ml. of sterile solution areprepared as follows:

Each ml. Total, gms. 57.5 mg. cytarabine hydrochloride 1380 5 mg. sodiumcitrate 9.45 mg. benzyl alcohol 227 2.3 mg. sodium bisulfite 55.2 Sodiumhydroxide (50% aqueous solution), q.s.

Water for injection, q.s. ad. 24000 ml.

Directi0ns.Dissolve the principal active ingredient, sodium citrate andbenzyl alcohol in 2,000 ml. water. Add the sodium bisulfite and adjustto pH 7.0 with the alkali. Make up to volume. Sterile filter the whole.Fill into 10 ml. sterile vials.

What is claimed is:

1. A process of treating herpes simplex in affected humans and animalswhich comprises the topical administration to said subjects of a topicalpharmaceutical preparation comprising as principal active ingredientfrom about 0.5 to about 2.5 by weight of a member selected from thegroup consisting of I-B-D-arabinofuranosylcytosine and a non-toxic acidaddition salt thereof and as supplementary active ingredient from about0.5 to about 2.5% by weight of 5-iodo-2-deoxyuridine.

2. A process of treating herpes simplex in affected humans and animalswhich comprises the topical administration to said subjects of aneffective amount of a member selected from the group consisting ofl-B-D- arabinofuranosylcytosine and a non-toxic acid addition saltthereof dispersed in a topical pharmaceutical carrier.

3. A process of treating herpes simplex in affected humans and animalswhich comprises the topical administration to said subjects of apharmaceutical preparation comprising from about 0.5 to about 2.5% byweight of a member selected from the group consisting of l-fi-D-arabinofuranosylcytosine and a non-toxic acid addition salt thereofdispersed in a topical pharmaceutical carrier.

5 6 4. The process of claim 3 in which the pharmaceutical ReferencesCited preparation comprises from about 0.5 to about 2.5% by UNITEDSTATES PATENTS Weight of a member selected from the group consisting of1-,8-D-arabinofuranosylcytosine and a non-toxic acid 3116282 12/1963Hunter 260-2115 addition salt thereof, butler salts providing a pH of 5about 7.4, an isotonic agent, and a liquid topical ALBERT MEYERS PllmwyExammer' pharmaceutical carrier. 1. GOLDBERG, Assistant Examiner.

2. A PROCESS OF TREATING HERPES SIMPLEX IN AFFECTED HUMANS AND ANIMALSWHICH COMPRISES THE TOPICAL ADMINISTRATION TO SAID SUBJECTS OF ANEFFECTIVE AMOUNT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF1-B-DARABINOFURANOSYLCYTOSINE AND A NON-TOXIC ACID ADDITION SALT THEREOFDISPERSED IN A TOPICAL PHARMACEUTICAL CARRIER.